Biomarker discovery and new insights into the pathophysiology of heart failure with reduced ejection fraction (HFrEF) may emerge from recent advances in high-throughput urinary proteomics. This could lead to improved diagnosis, risk stratification and management of HFrEF. Urine samples were analyzed by on-line capillary electrophoresis coupled to electrospray ionization micro time-of-flight mass spectrometry (CE-MS) to generate individual urinary proteome profiles. In an initial biomarker discovery cohort, analysis of urinary proteome profiles from 33 HFrEF patients and 29 age- and sex-matched individuals without HFrEF resulted in identification of 103 peptides that were significantly differentially excreted in HFrEF. These 103 peptides were used to establish the support vector machine-based HFrEF classifier HFrEF103. In a subsequent validation cohort, HFrEF103 very accurately (area under the curve, AUC = 0.972) discriminated between HFrEF patients (N = 94, sensitivity = 93.6%) and control individuals with and without impaired renal function and hypertension (N = 552, specificity = 92.9%). Interestingly, HFrEF103 showed low sensitivity (12.6%) in individuals with diastolic left ventricular dysfunction (N = 176). The HFrEF-related peptide biomarkers mainly included fragments of fibrillar type I and III collagen but also, e.g., of fibrinogen beta and alpha-1-antitrypsin. CE-MS based urine proteome analysis served as a sensitive tool to determine a vast array of HFrEF-related urinary peptide biomarkers which might help improving our understanding and diagnosis of heart failure.

BACKGROUND: Patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction commonly experience reduced exercise capacity. Physical training improves exercise capacity in these patients, but whether the underlying effects of exercise are a result of central hemodynamic or peripheral improvement is unclear. This study assessed whether exercise training reduces left ventricular filling pressure measured during exercise in patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction. METHODS: Between March 2019 and June 2022, patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction were randomly assigned (1:1) to a 12-week (3 h/wk) supervised, moderate-intensity exercise training program or continued usual activity. The primary outcome was the change in invasively measured pulmonary capillary wedge pressure during mild exercise (25 W) from baseline to week 12. Pressure tracings were analyzed offline by a blinded investigator. Secondary outcomes included changes in peak oxygen consumption, cardiac index, quality of life, echocardiographic indices of diastolic function, and natriuretic peptides. RESULTS: Of 59 patients randomized (mean age, 58.1 [12.2] years; 27% women), 51 (86%) completed all follow-up assessments. At week 12, the change in 25-W pulmonary capillary wedge pressure was –2.8 (6.8) mm Hg in the exercise group, compared with +1.2 (4.9) mm Hg in the usual-activity group (between-group difference, 4.0 mm Hg [95% CI, 0.7–7.3]; P =0.018). Peak oxygen consumption improved by +1.8 (2.0) mL·kg⁻¹·min⁻¹ in the exercise group versus –0.3 (3.1) mL·kg⁻¹·min⁻¹ in the usual-activity group ( P =0.005). Exercise training improved the ventilatory efficiency (V _E /VCO ₂ ) slope compared with usual activity (between-group difference, 2.0 [95% CI, 0.6–3.5]; P =0.006). Peak cardiac index improved by +0.38 (1.38) L·min⁻¹·m⁻² in exercise versus –0.85 (1.20) L·min⁻¹·m⁻² in the usual-activity group ( P =0.002). Change in overall Kansas City Cardiomyopathy Questionnaire score was similar between groups. However, the change in physical limitation scores (+8.4 [12.0] points in exercise versus +0.7 [6.8] points in usual-activity group; P =0.034) and quality-of-life scores (+8.7 [18.0] points in exercise versus 0.7 [4.0] points in usual-activity group; P =0.01) differed significantly. There were no significant changes in diastolic function assessed by echocardiography or in natriuretic peptides. CONCLUSIONS: In patients with hypertrophic cardiomyopathy without left ventricular outflow tract obstruction, a 12-week moderate-intensity exercise training program resulted in reduced left ventricular filling pressures at mild exertion and improved exercise performance. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03537183.

(1) Background: Kidney and cardiovascular diseases are responsible for a large fraction of population morbidity and mortality. Early, targeted, personalized intervention represents the ideal approach to cope with this challenge. Proteomic/peptidomic changes are largely responsible for the onset and progression of these diseases and should hold information about the optimal means of treatment and prevention. (2) Methods: We investigated the prediction of renal or cardiovascular events using previously defined urinary peptidomic classifiers CKD273, HF2, and CAD160 in a cohort of 5585 subjects, in a retrospective study. (3) Results: We have demonstrated a highly significant prediction of events, with an HR of 2.59, 1.71, and 4.12 for HF, CAD, and CKD, respectively. We applied in silico treatment, implementing on each patient’s urinary profile changes to the classifiers corresponding to exactly defined peptide abundance changes, following commonly used interventions (MRA, SGLT2i, DPP4i, ARB, GLP1RA, olive oil, and exercise), as defined in previous studies. Applying the proteomic classifiers after the in silico treatment indicated the individual benefits of specific interventions on a personalized level. (4) Conclusions: The in silico evaluation may provide information on the future impact of specific drugs and interventions on endpoints, opening the door to a precision-based medicine approach. An investigation into the extent of the benefit of this approach in a prospective clinical trial is warranted.

BACKGROUND: TAP-IT (Thoracentesis to Alleviate Cardiac Pleural Effusion–Interventional Trial) investigated the effect of therapeutic thoracentesis in addition to standard medical therapy in patients with acute heart failure and sizeable pleural effusion. METHODS: This multicenter, unblinded, randomized controlled trial, conducted between August 31, 2021, and March 22, 2024, included patients with acute heart failure, left ventricular ejection fraction ≤45%, and non-negligible pleural effusion. Patients with very large effusions (more than two-thirds of the hemithorax) were excluded. Participants were randomly assigned 1:1 to upfront ultrasound-guided pleural pigtail catheter thoracentesis in addition to standard medical therapy or standard medical therapy alone. The primary outcome was days alive out of the hospital over the following 90 days; key secondary outcomes included length of admission and 90-day all-cause mortality. All outcomes were analyzed according to the intention-to-treat principle. RESULTS: A total of 135 patients (median age, 81 years [25th; 75th percentile, 75; 83]; 33% female; median left ventricular ejection fraction, 25% [25th; 75th percentile, 20%; 35%]) were randomized to either thoracentesis (n=68) or standard medical therapy (n=67). The thoracentesis group had a median of 84 days (77; 86) alive out of the hospital over the following 90 days compared with 82 days (73; 86) in the control group ( P =0.42). The mortality rate was 13% in both groups, with no difference in survival probability ( P =0.90). There were no differences in the duration of the index admission (control group median, 5 days [3; 8]; thoracentesis group median, 5 days [3; 7], P =0.69). Major complications occurred in 1% of thoracenteses performed during the study period. CONCLUSIONS: For patients with acute heart failure and pleural effusion, a strategy of upfront routine thoracentesis in addition to standard medical therapy did not increase days alive out of the hospital for 90 days, all-cause mortality, or duration of index admission. The current findings lay the groundwork for future research to confirm the results. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05017753.

BACKGROUND: Pleural effusion is present in 50% to 80% of patients with acute heart failure, depending on image modality. We aim to describe the association between the presence and size of pleural effusion and central hemodynamics, including pulmonary capillary wedge pressure (PCWP) in an advanced heart failure population. METHODS: An observational, cross-sectional study in a cohort of patients with advanced heart failure (left ventricular ejection fraction ≤45%) who underwent right heart catheterization at The Department of Cardiology at Copenhagen University Hospital, Rigshospitalet, Denmark, between January 1, 2002 and October 31, 2020. The presence and size of pleural effusion were determined by a semiquantitative score of chest x -rays or computed tomography scans performed within 2 days of right heart catheterization. RESULTS: In 346 patients (50±13 years; 78% males) with median left ventricular ejection fraction of 20% (15–25), we identified 162 (47%) with pleural effusion. The pleural effusion size was medium in 38 (24%) and large in 30 (19%). Patients with pleural effusion had a 4.3 mm Hg (2.5–6.1) higher PCWP and 2.4 mm Hg (1.2–3.6) higher central venous pressure ( P <0.001 for both). Patients with a medium/large pleural effusion had statistically significantly higher filling pressures than patients with a small effusion. Higher PCWP (odds ratio [OR], 1.06 [1.03–1.10]) and central venous pressure (OR, 1.09 [1.05–1.15]) were associated with pleural effusion in multivariable logistic regression adjusted for age, sex, and heart failure medications ( P <0.001 for both). In a subgroup of 204 (63%) patients with serum albumin data, PCWP (OR, 1.06 [1.01–1.11]; P =0.032), central venous pressure (OR, 1.14 [1.06–1.23]; P <0.001) and serum albumin level (OR, 0.89 [0.83–0.95]; P <0.001) were independently associated with the presence of a medium/large-sized pleural effusion. CONCLUSIONS: In patients with left ventricular ejection fraction ≤45% undergoing right heart catheterization as part of advanced heart failure work-up, pleural effusion was associated with higher PCWP and central venous pressure and lower serum albumin.

Insight into predictors of cardiac involvement in inflammatory myopathies is sparse. A negative prognostic role of anti-mitochondrial antibodies (AMA) has been noticed and is supported by the current case. We describe a male patient who at the age 40 suffered a cardiac arrest and over the following months experienced progressive heart failure, arrhythmias and proximal muscle weakness. Clinical, genetic and serologic testing and repeated imaging- and histopathological investigations resulted in a diagnosis of AMA-associated, necrotizing, inflammatory myositis with cardiac involvement. Besides a cardiac resynchronization therapy defibrillator, heart failure and antiarrhythmic drugs the patient received successive immunosuppressants, which improved skeletal muscle strength but not cardiac disease progression. At age 45 he died from end-stage heart failure. Clinicians must be aware of AMA-associated myositis as a cause of unclarified heart disease, even in patients with initially sparse extra-cardiac manifestations. Further knowledge of treatment strategies is highly needed for this disease entity.